Breaking the vicious cycle of cellular senescence and ROS via a mitochondrial-targeted hydrogel for aged bone regeneration

• The mitochondrial-targeted hydrogel (TPG@ChSMA) was developed. • TPG@ChSMA hydrogel mediated the SIRT1/PI3K/AKT signalling pathways to break the vicious cycle of cellular senescence and ROS. • TPG@ChSMA scaffold significantly improved bone regeneration in osteoporosis rat models. • TPG@ChSMA scaffold had a potential for repairing aging bone defects by ameliorating cellular senescence and ROS levels. Mitochondrial dysfunction and redox imbalance in senescent cells hinder bone repair during aging. Thus, strategies to restore mitochondrial function and reduce reactive oxygen species (ROS) levels could effectively counteract cellular senescence and promote osteogenesis. In this study, we developed a Chondroitin Sulfate Methacryloyl (ChSMA) composite hydrogel scaffold (TPG@ChSMA) incorporating tea polyphenol-reduced graphene (TPG). The mitochondrial-targeted antioxidant TPG served as a crucial agent to balance ROS levels and enhance mitochondrial function in senescent cells, while ChSMA promoted bone formation regulation and provided a stabilized ossification platform. The mitochondrial-targeted composite scaffold mediated ROS elimination and counteracted cellular senescence via the SIRT1/PI3K/AKT pathway in vitro . Therefore, it played a pivotal role in maintaining cellular homeostasis by reducing oxidative stress and promoting cell survival. Concurrently, the ERK1/2 pathway was activated to facilitate bone differentiation. The combined activation of these pathways created a microenvironment conducive to regeneration that significantly enhanced the osteogenic differentiation potential of senescent BMSCs. The TPG@ChSMA scaffold demonstrated significant efficacy in promoting bone regeneration and reducing the expression of senescence-associated marker p16 in an osteoporosis rat model induced by bilateral ovariectomy. Overall, these findings underscore the potential of mitochondrial-targeted therapeutic strategies to repair aging bone defects by mitigating ROS levels and alleviating cellular senescence.